The objective of the proposed Program Project Grant is to study the molecular neurobiological mechanisms underlying opiate and cocaine addiction. The program of research contains two major strengths. First, is the multidisciplinary nature of the proposed research. Each research area represents an integration of molecular, biochemical, electrophysiological, neurochemical, and behavioral levels of analysis aimed at obtaining a more complete understanding of the biological basis of drug addiction. Second, is the integration of the proposed basic science research with a well- established clinical research program in drug abuse currently being conducted within these facilities. The proposed studies focus on two major areas of investigation of great importance to the field of drug abuse: Part A. Mechanisms Underlying Opiate Tolerance, Dependence, and Withdrawal; and Part B. Mechanisms Underlying the Long-Term Actions Of Cocaine and Opiates on the Mesolimbio Dopamine System. Four projects are included under Part A. Projects 1 and 2 represent a continuation of a productive and growing collaboration among the laboratories of Drs. Nestler, Aghajanian, Duman, Alreja, Moghaddam, Deutch, Elsworth, and Roth on the molecular and cellular mechanisms by which opiates regulate locus coeruleus neurons acutely and chronically. Project 3, carried out by Drs. Davis, Kosten, Krystal, and Taylor, represents a series of behavioral assessments of opiate dependence and withdrawal that are derived from, and complement, the studies in Projects 1 and 2. Project 4 consists of three pilot studies, conducted by Drs. Kosten, Rosen, and Oliveto, to study the clinical ramifications of the basic neurobiological research included in Projects 1 through 3. Three Projects are included under Part B. Project 5 is focused on the regulation of neuropeptide systems by cocaine and opiate exposure in the mesolimbic dopamine system by use of molecular, neurochemical, and behavioral approaches, and will be conducted by Drs. Duman, Sevarino, Roth, Bradberry, Deutch, and Elsworth. Project 6, also an integration of molecular, neurochemical, and behavioral approaches, is aimed at studying the role of the cyclic AMP and glutamate systems in cocaine and opiate reward mechanisms, and will be conducted by Drs. Nestler, Miserendino, Roth, Duman, Moghaddam, Bradberry, Kosten, Deutch, and Elsworth. Project 7, derived in part from behavioral studies in Project 6, is designed to establish an objective measure of cocaine effects in clinical populations. The proposed Program Project Grant represents a natural development of the growth and continuing success of basic drug addiction research within our group. It will foster and further strengthen our multidisciplinary research program into the molecular neurobiological mechanisms underlying drug addiction.